Immunoglobulin light chain amyloidosis is a fatal protein aggregation disease caused by deposition of monoclonal light chains that interfere with organ function and result ultimately in death. High dose chemotherapy has been increasingly used to treat patients with amyloidosis; however it carries a treatment-related mortality of 15% and can result in prolonged hospitalization for patients. HYPOTHESIS: The technique of autologous stem cell transplantation has not been rigorously tested in a phase III trial design and compared with the best available low dose chemotherapy. We propose the following specific aims to test the hypothesis. In Specific Aim 1, we plan to assess the overall response rate of patients with AL who are treated with myeloablative chemotherapy followed by stem cell transplantation compared to those who receive only low dose chemotherapy through a randomized clinical trial. We hypothesize that the use of high dose chemotherapy with stem cell transplantation will result in an ultimate doubling of the response rate. In Specific Aim 2 we will determine the clonal relationship and diversification dynamics between peripheral B cells and the neoplastic population in the bone marrow of AL patients in the trial by genetic (experimental) and mathematical analysis. We will also determine the frequency of clonal precursor B-cells in the periphery (and stem cell autografts) of AL patients and assess its impact on clinical outcome and survival. We hypothesize that the burden of B cell precursors in the periphery determines clinical outcome. In Specific Aim 3 we will determine the kinetics of amyloid formation in a subset of AL patients enrolled in the clinical trial. We hypothesize that those patients who have a reduction in free light chain levels and improvement of renal function response after treatment will have slower amyloid formation rates compared to patients with a reduction of free light chain but no improvement in renal function. The decrease in monoclonal light chain protein may permit the catabolism of deposited amyloid fibrils with resultant improvement in organ function, over time. The significance of this study lies in the fact that this represents the first randomized study of high dose therapy for the management of amyloidosis in the USA with a definable endpoint and statistical power to test a relevant hypothesis in the treatment of these patients. In addition, the analysis of clonal precursor B cells in the periphery and kinetics of amyloid formation of the monoclonal light chain will allow us to define and determine the mechanisms of disease progression and response to therapy. [unreadable] [unreadable]